Drugs for the acute treatment of migraine in children and adolescents

Lawrence Richer; Lori Billinghurst; Meghan A Linsdell; Kelly Russell; Ben Vandermeer; Ellen T Crumley; Tamara Durec; Terry P Klassen; Lisa Hartling

doi:10.1002/14651858.CD005220.pub2

. 2016 Apr 19;2016(4):CD005220. doi: 10.1002/14651858.CD005220.pub2

Drugs for the acute treatment of migraine in children and adolescents

Lawrence Richer ^1,^✉, Lori Billinghurst ², Meghan A Linsdell ³, Kelly Russell ⁴, Ben Vandermeer ⁵, Ellen T Crumley ⁶, Tamara Durec ⁷, Terry P Klassen ⁸, Lisa Hartling ⁵

Editor: Cochrane Pain, Palliative and Supportive Care Group

PMCID: PMC6516975 PMID: 27091010

Abstract

Background

Numerous medications are available for the acute treatment of migraine in adults, and some have now been approved for use in children and adolescents in the ambulatory setting. A systematic review of acute treatment of migraine medication trials in children and adolescents will help clinicians make evidence‐informed management choices.

Objectives

To assess the effects of pharmacological interventions by any route of administration versus placebo for migraine in children and adolescents 17 years of age or less. For the purposes of this review, children were defined as under 12 years of age and adolescents 12 to 17 years of age.

Search methods

We searched seven bibliographic databases and four clinical trial registers as well as gray literature for studies through February 2016.

Selection criteria

We included prospective randomized controlled clinical trials of children and adolescents with migraine, comparing acute symptom relieving migraine medications with placebo in the ambulatory setting.

Data collection and analysis

Two reviewers screened titles and abstracts and reviewed the full text of potentially eligible studies. Two independent reviewers extracted data for studies meeting inclusion criteria. We calculated the risk ratios (RRs) and number needed to treat for an additional beneficial outcome (NNTB) for dichotomous data. We calculated the risk difference (RD) and number needed to treat for an additional harmful outcome (NNTH) for proportions of adverse events. The percentage of pain‐free patients at two hours was the primary efficacy outcome measure. We used adverse events to evaluate safety and tolerability. Secondary outcome measures included headache relief, use of rescue medication, headache recurrence, presence of nausea, and presence of vomiting. We assessed the evidence using GRADE (Grading of Recommendations Assessment, Development and Evaluation) and created 'Summary of findings' tables.

Main results

We identified a total of 27 randomized controlled trials (RCTs) of migraine symptom‐relieving medications, in which 9158 children and adolescents were enrolled and 7630 (range of mean age between 8.2 and 14.7 years) received medication. Twenty‐four studies focused on drugs in the triptan class, including almotriptan, eletriptan, naratriptan, rizatriptan, sumatriptan, sumatriptan + naproxen sodium, and zolmitriptan. Other medications studied included paracetamol (acetaminophen), ibuprofen, and dihydroergotamine (DHE). More than half of the studies evaluated sumatriptan. All but one study reported adverse event data. Most studies presented a low or unclear risk of bias, and the overall quality of evidence, according to GRADE criteria, was low to moderate, downgraded mostly due to imprecision and inconsistency. Ibuprofen was more effective than placebo for producing pain freedom at two hours in two small studies that included 162 children (RR 1.87, 95% confidence interval (CI) 1.15 to 3.04) with low quality evidence (due to imprecision). Paracetamol was not superior to placebo in one small study of 80 children. Triptans as a class of medication were superior to placebo in producing pain freedom in 3 studies involving 273 children (RR 1.67, 95% CI 1.06 to 2.62, NNTB 13) (moderate quality evidence) and 21 studies involving 7026 adolescents (RR 1.32, 95% CI 1.19 to 1.47, NNTB 6) (moderate quality evidence). There was no significant difference in the effect sizes between studies involving children versus adolescents. Triptans were associated with an increased risk of minor (non‐serious) adverse events in adolescents (RD 0.13, 95% CI 0.08 to 0.18, NNTH 8), but studies did not report any serious adverse events. The risk of minor adverse events was not significant in children (RD 0.06, 95% CI − 0.04 to 0.17, NNTH 17). Sumatriptan plus naproxen sodium was superior to placebo in one study involving 490 adolescents (RR 3.25, 95% CI 1.78 to 5.94, NNTB 6) (moderate quality evidence). Oral dihydroergotamine was not superior to placebo in one small study involving 13 children.

Authors' conclusions

Low quality evidence from two small trials shows that ibuprofen appears to improve pain freedom for the acute treatment of children with migraine. We have only limited information on adverse events associated with ibuprofen in the trials included in this review. Triptans as a class are also effective at providing pain freedom in children and adolescents but are associated with higher rates of minor adverse events. Sumatriptan plus naproxen sodium is also effective in treating adolescents with migraine.

Plain language summary

Drugs for the acute treatment of migraine in children and adolescents

Background and review question

Migraine is a painful and debilitating disorder that is common in children (under 12 years of age) and adolescents (12 to 17 years of age). Common symptoms reported during a migraine attack are headache, nausea, vomiting, and sensitivity to light and sound. Many treatments for migraine are available, of which the most common are paracetamol (also known as acetaminophen), ibuprofen and other anti‐inflammatories, and triptans. Not all triptan medications are approved for use in children or adolescents, and approvals vary from country to country.

Study characteristics

In our review, we looked at 27 randomized controlled trials of drugs compared to placebo to find out which treatments were effective at providing pain freedom two hours after treatment. We also wanted to know what side effects might be caused by the treatments. A total of 7630 children received medication in the studies. The evidence is current to February 2016. Each study had between 13 and 888 participants. Their average age was 12.9 years and ranged from 8.2 to 14.7 years. Nineteen of the studies were funded by the drug manufacturer.

Key results

Ibuprofen appears to be effective in treating children with migraine, but the evidence is limited to only two small trials. Ibuprofen is readily available and inexpensive, making it an excellent first choice for migraine treatment. Paracetamol was not shown to be effective in providing pain freedom in children, but we only found one small study. Triptans are a type of medication designed specifically to treat migraine and are often effective at providing greater pain freedom in children and adolescents. The triptans examined in children included rizatriptan and sumatriptan, while almotriptan, eletriptan, naratriptan, rizatriptan, sumatriptan, and zolmitriptan were examined in adolescents. The combination of sumatriptan plus naproxen sodium is also effective at treating adolescents with migraine. Overall, there is a risk that the triptan medications may cause minor unwanted side effects like taste disturbance, nasal symptoms, dizziness, fatigue, low energy, nausea, or vomiting. The studies did not report any serious side effects.

Quality of the evidence

The overall quality of the evidence provided by the review was moderate for the triptans, but low for paracetamol and ibuprofen, as we only identified a few studies. More studies need to look at the effects of each of the migraine treatments in children and adolescents separately.

Summary of findings

Background

Migraine is a common and disabling disease, affecting 3% to 10% of children and adolescents (Stovner 2007). Children as young as two years of age may be affected, and most adults with migraine have their first headache in early childhood or adolescence (Bille 1997). Quality‐of‐life studies indicate that migraine has a significant negative impact on a child (Powers 2003; Powers 2004). Indeed, migraines can be a tremendous source of anxiety for children, adolescents, and their parents, disrupting both school obligations and parental work responsibilities. These concerns may be amplified when there is uncertainty on the physician's part as to the best treatment.

The International Classification of Headache Disorders, 3^rd edition, beta version (ICHD‐3 beta), provides the most accepted and current definition of migraine. The presence of headache, often associated with nausea, vomiting, or both is common to adults, adolescents, and children with migraine. However, the criteria acknowledge that children and adolescents' migraines may be shorter but will last at least two hours, and the pain may be bilateral over the frontotemporal head regions or non‐pulsatile. Adolescents, like adults, will usually begin to report unilateral pulsatile pain. The presence of photophobia and phonophobia may need to be inferred from behaviour such as a preference for a quiet and dimly lit room during a migraine attack.

Treatments for migraine include symptom‐relieving and preventive strategies. Preventive medications are used to reduce the frequency and severity of migraine attacks. Symptom‐relieving therapies commonly aim to eliminate head pain and reduce the symptoms associated with migraine, including nausea, phonophobia, and photophobia. Oral analgesics such as paracetamol and ibuprofen are the mainstay of acute therapy for migraine in children and adolescents (Hämäläinen 2002). However, other agents such as ergot derivatives (e.g. dihydroergotamine) and the serotonin 1b/1d receptor agonists (triptans) have demonstrated efficacy in adults. Many of these medications have now been studied in children and adolescents, and some are approved for use in the pediatric age group. A practice parameter on this topic has been published by the American Academy of Neurology Quality Standards Subcommittee and the Practice Committee of the Child Neurology Society (Lewis 2004). This systematic review will summarize and update the evidence base and provide a meta‐analysis of the data.

Objectives

Methods

Criteria for considering studies for this review

Types of studies

We included all prospective, placebo‐controlled trials of pharmacological interventions for symptomatic or acute treatment of migraine in children and adolescents in the outpatient setting if allocation to treatment groups was randomized (see Differences between protocol and review). We included studies regardless of design (i.e. parallel‐group or cross‐over), publication status, or language of publication. We included cross‐over studies, as migraine is an episodic disorder, and we did not expect any carry‐over or period effects (see Differences between protocol and review). We excluded non‐placebo‐controlled studies, concurrent cohort comparisons and other quasi‐ or non‐experimental designs.

Types of participants

We included studies involving pediatric participants 17 years of age or less with a diagnosis of migraine with or without aura. For the purposes of the review, we defined children as under 12 years of age and adolescents as 12 to 17 years of age (see Differences between protocol and review). We recorded inclusion age criteria, including median and mean age of subjects. We excluded studies involving both pediatric and adult patients unless they reported results separately for the pediatric patients. We analyzed separately the data from studies that included both children and adolescents when possible. If studies did not report the data separately, we used the mean age as a surrogate. If the mean age in the study was less than 12 years, we considered the study population to be of predominantly childhood age. If the mean age was greater than or equal to 12 years, we considered the study population to be of predominantly adolescent age.

Migraine is defined by clinical symptoms and signs in the 3^rd edition of the International Classification of Headache Disorders, beta version (ICHD‐3 beta). ICHD‐3 beta includes revised comments for the diagnosis of migraine in children and adolescents, including shorter duration of headache (2 to 72 hours), bilateral frontotemporal location, and the presence of photophobia and phonophobia as inferred from behaviour. There have been two other versions of the International Classification of Headache Disorder and a proposed revision of the 1988 criteria in the context of children or adolescents (IHS 1988; ICHD‐2; Winner 1995). We included a study in this review if investigators used any version of the International Headache Society classification systems above or the proposed revision for pediatrics for the diagnosis of migraine with or without aura.

Types of interventions

We included studies allocating participants to receive a pharmacological intervention by any route of administration for symptomatic acute treatment of a migraine attack. Acceptable comparator groups included placebo or other active drug treatments. We identified the use of preventive medication and examined this in subgroup analysis, but discontinuation was not required for inclusion.

Types of outcome measures

We chose outcomes to assess both efficacy and safety. We selected the primary efficacy outcome based on the suggested guidelines for controlled trials of drugs in migraine (Tfelt‐Hansen 2012). The primary outcome for safety was based on the report of adverse events. All outcome measures were reported for the treatment of a single attack (see Differences between protocol and review).

Primary outcomes

The primary outcome measure for efficacy was the percentage of pain‐free participants at two hours; we defined pain freedom as the absence of pain at two hours before the use of additional or rescue medication (see Differences between protocol and review). Headache relief is a frequently used primary outcome measure that is variably defined based on the scale used to assess pain. For example, if using the four level scale of none, mild, moderate, or severe pain, investigators or physicians may define headache relief as a decrease in pain from moderate or severe to mild or none. Some in the migraine research community have challenged the use of headache relief as a primary outcome measure; for example, migraine sufferers generally do not consider headache relief a success and expect pain freedom from an intervention (Davies 2000; Lipton 2002). Given these considerations, we classified headache relief as a secondary outcome measure (see Differences between protocol and review).

We used the percentage of participants with any adverse event(s) as the primary safety outcome measure, and this was required for inclusion in the analysis (see Differences between protocol and review). We defined adverse events as any unwanted effect that occurred during treatment. We also documented the proportion of participants reporting any serious adverse events when possible. Serious adverse events included death, any life‐threatening condition, hospitalization, disability or permanent damage, required intervention to prevent permanent damage, or any other important medical event that could jeopardize the participant or require medical or surgical intervention.

Some aspects of the original protocol were not necessary to implement given the way studies reported outcome data. We document these considerations in the Differences between protocol and review section.

Secondary outcomes

We assessed the following secondary outcome measures.

Headache relief (headache response): the percentage of participants with headache relief at two hours is typically defined as a decrease in headache intensity from severe or moderate to mild or none at two hours prior to the use of rescue medication. When studies used alternate definitions of pain intensity (e.g. numerical scale), they needed to describe a level of relief that would be meaningful to a participant and to reflect a decrease in headache intensity similar to that assumed in the above definition.
Rescue medication: the percentage of participants taking rescue medication at two hours or earlier to a maximum of six hours after the test drug. The definition of rescue medication was variable and often included any use of medication to treat the recurrence of headache within a specified timeframe (i.e. usually 24 hours). For the purposes of the review, rescue medication was defined as the use of any medication between 2 and 24 hours.
Headache recurrence: the percentage of participants who were initially pain‐free or achieved the study primary outcome of headache relief within 2 hours without the use of rescue medication but who experienced recurrence of any headache from 2 to 48 hours.
Presence of nausea: percentage of participants with nausea at two hours after taking the test drug.
Presence of vomiting: percentage of participants with vomiting within two hours of taking the test drug.

We did not include participant preference, presence of photophobia, or presence of phonophobia in the analysis as originally planned in the protocol (see Differences between protocol and review).

Search methods for identification of studies

We conducted a search of electronic databases in collaboration with a research librarian using search strategies to identify the highest level of evidence for the topic. In addition, we manually searched other sources listed below.

Electronic searches

We systematically searched the following databases:

Cochrane Central Register of Controlled Trials (CENTRAL) (1991 to 2013, Issue 3).
OvidSP MEDLINE (1946 to February 2016).
Ovid MEDLINE In‐Process & Other Non‐Indexed Citations (2012 to February 2016).
EMBASE (1980 to February 2016).
Database of Abstracts and Reviews of Effects (1991 to April 2013).
International Pharmaceutical Abstracts (1970 to April 2013).
PsycINFO (1806 to April 2013).
EBSCOhost CINAHL (Cumulative Index of Nursing and Allied Health) (1937 to April 2013).

The search strategies used a combination of text words and medical subject headings (MeSH), adapted for each database searched: concepts included migraine, headache, cephalgia or cephalalgia, drug therapy, drug treatment, antimigraine therapy, antimigraine treatment, and treatment outcome, combined with drugs and acute treatments known to be used for migraine in children and adolescents. These terms were combined with a pediatric filter designed by the librarian (Lisa Tjosvold) of the Cochrane Child Health Field.

Complete search strategies are given in Appendix 1.

Searching other resources

We conducted a gray literature search including reviewing the reference lists of included studies and handsearching meeting abstracts from the American Headache Society and International Headache Society Scientific meetings. The review authors attempted to contact primary authors, experts in the area, and drug manufacturers (GlaxoSmithKline, AstraZeneca, Ortho‐McNeil, Merck, and Pfizer) for information on recent, ongoing, or unpublished trials. We searched ClinicalTrials.gov for new or ongoing studies and used Current Controlled Trials (www.controlled-trials.com) to search across multiple trial registries. GlaxoSmithKline (www.gsk-clinicalstudyregister.com) and AstraZeneca (www.astrazenecaclinicaltrials.com) have clinical trial registries and report on both published and unpublished studies.

Data collection and analysis

Selection of studies

We identified potentially relevant articles by reviewing the titles and abstracts from the original search. We considered studies with insufficient information in the title or abstract as potentially relevant articles for further assessment. We then reviewed the full text of potentially relevant studies for inclusion or exclusion. Two reviewers independently carried out both steps. A third, independent reviewer resolved any disagreements that arose between them.

Data extraction and management

One reviewer used a standardized data abstraction form to extract data, which a second reviewer then checked for accuracy and completeness. We recorded extracted data in Review Manager 5 (RevMan 2014). A third, independent reviewer resolved discrepancies.

Assessment of risk of bias in included studies

Two reviewers assessed risk of bias using the 'Risk of bias' table for each study. Reviewers assessed five domains before making a judgement: sequence generation, allocation concealment, blinding, incomplete outcome data, and selective reporting (Higgins 2011). We resolved any disagreements by discussion. We did not use the Jadad scale as planned in the protocol, as per current recommendations of the Cochrane Collaboration (Differences between protocol and review).

Assessment of quality of evidence in included studies

We assessed the overall quality of the evidence for each outcome using the GRADE system and included our assessment in the 'Summary of findings' tables in order to present the main findings of the review in a transparent and simple tabular format (GRADEPro 2015). In particular, we included key information concerning the quality of evidence, the magnitude of effect of the interventions examined, and the sum of available data on the main outcomes.

The GRADE system uses the following criteria for assigning a level of evidence.

High: further research is very unlikely to change our confidence in the estimate of effect.
Moderate: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low: any estimate of effect is very uncertain.

We decreased the grade if we found:

serious (− 1) or very serious (− 2) limitations to study quality;
important inconsistency(s) (− 1);
some (− 1) or major (− 2) uncertainty about directness;
imprecise or sparse data (− 1);
high probability of reporting bias (− 1).

'Summary of findings' table

We decided post hoc to include four 'Summary of findings' tables to present the main findings in a transparent and simple tabular format. In particular, we included key information concerning the quality of evidence, the magnitude of effect of the interventions examined, and the sum of available data on the outcomes pain freedom at 2 hours and adverse events, for the four main comparisons.

Measures of treatment effect

We reported the risk ratio (RR) for all primary and secondary efficacy outcome measures with 95% confidence intervals (CIs) as well as the number needed to treat for an additional beneficial outcome (NNTB). We reported the risk difference (RD) with 95% CIs for the adverse events as the primary measure of harm as well as the number needed to treat for an additional harmful outcome (NNTH).

Unit of analysis issues

We included cross‐over trials with binary outcomes in the analysis (Curtin 2002). None of the cross‐over trials reported any significant carry‐over or period effects, and none would be expected based on the acute episodic nature of migraine.

Dealing with missing data

We only analyzed the available data for all outcomes. We assessed the possibility of missing studies as described below (see Assessment of reporting biases). We considered variability in the reporting of outcomes to be random.

Assessment of heterogeneity

We assessed heterogeneity using the I² statistic. We interpreted the I² statistic as suggested in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).

Assessment of reporting biases

We assessed reporting biases qualitatively by visually examining the funnel plot and quantitatively using a modified version of Egger's test (Egger 1997; Harbord 2006), as implemented in the metabias module for Stata statistical software package on the triptan versus placebo studies in adolescents using the pain‐free outcome (Stata 14).

Data synthesis

We pooled studies using a Mantel‐Haenszel, random‐effects model. We pooled dichotomous outcomes, and calculated RRs with 95% CIs. We calculated the number needed to treat for an additional beneficial outcome (NNTB) for RRs of the primary outcome that were statistically significant. For adverse events, we combined data combined using RDs with 95% CIs. We calculated the number needed to treat for an additional harmful outcome (NNTH) for RDs of adverse events that were statistically significant. We included studies with small sample sizes and imprecise effect estimates, but we graded them lower for quality and weighted them accordingly in the meta‐analyses.

We combined trials of cross‐over design with parallel group trials in the meta‐analysis. We included outcome measures from each intervention period in the analysis as if the trial were a parallel group trial. We also included three‐way cross‐over studies with two intervention periods and one placebo period as if they were a parallel group trial, but we divided the placebo period in two to avoid double counting the placebo interventions. Paired analysis was not possible for any of the included studies (see Differences between protocol and review). This method of including cross‐over studies will tend to produce wider confidence intervals and is considered a more conservative assessment of treatment effect given that these studies will receive a lower weight in the meta‐analyses. We included study design in the sensitivity analysis to assess the influence of cross‐over design on our final conclusions.

Subgroup analysis and investigation of heterogeneity

We used the I² statistic to determine the presence of heterogeneity and test for subgroup differences as implemented in RevMan, used to prepare this review (Higgins 2002; RevMan 2014). We performed all subgroup analyses for the pain‐free outcome measure using the placebo‐controlled studies of triptan medications versus placebo in adolescents (except for the age‐based subgroup analysis).

Post hoc subgroup analyses included the following.

Intranasal route.
Preventive medication permitted during the study.

Sensitivity analysis

We examined potential sources of heterogeneity using the following a priori sensitivity analyses (see Differences between protocol and review).

Allocation concealment (low, unclear, or high risk of bias).
Cross‐over versus parallel‐group study design.
Source of funding (pharmaceutical, non‐pharmaceutical, or unclear).
Reported in a peer‐reviewed indexed journal.
Small sample size ≤ 50.

We performed all sensitivity analyses for the pain‐free primary outcome using the studies of triptan medications versus placebo in adolescents.

Results

Description of studies

See Characteristics of included studies, Characteristics of excluded studies, Characteristics of ongoing studies.

Results of the search

The literature search and review of the gray literature yielded 15,811 unique citations, 379 of which we assessed as full‐text articles for eligibility. Some of our data requests to manufacturers were met with referrals to trial registry websites or data were not made available. A total of 27 randomized placebo‐controlled trials of acute drug therapy for migraine met our inclusion criteria (Figure 1).

Included studies

The mean age of inclusion was 12.9 years with a range of means between 8.2 and 14.7 years. The minimum age of inclusion was 4 years in one study (Hämäläinen 1997a), and the maximum age for inclusion was 18 years in two studies (Evers 2006; Hämäläinen 1997b). Three studies included only children under 12 (Hämäläinen 2002; Lewis 2002; Ueberall 1999), and one study reported data for children and adolescents separately (Ho 2012). Six studies included children and adolescents, but they did not report the data separately (Ahonen 2004; Ahonen 2006; Evers 2006; Hämäläinen 1997a; Hämäläinen 1997b; Hämäläinen 1997c). Participants in two of the studies reporting children and adolescents combined had a mean age of less than 12 years and were included in the analysis as studies of predominantly children (Hämäläinen 1997a; Hämäläinen 1997c). Participants in the remaining four studies where children and adolescents were combined had a mean age of greater than 12 years, and we considered them to be studies of predominantly adolescents for the analysis. Finally, 17 studies included only adolescents over the age of 12 years (Callenbach 2007; Derosier 2012; Fujita 2014; Lewis 2007; Linder 2008; NCT01211145; Rothner 1997; Rothner 1999a; Rothner 1999b; Rothner 1999c; Rothner 2006; Visser 2004a; Winner 1997; Winner 2000; Winner 2002; Winner 2006; Winner 2007). The mean number of participants randomized was 359 with a range of 13 to 888. We summarize the characteristics of included studies in Table 5, and we summarize the individual studies in Table 6. We provide more details, including a risk of bias assessment, in Characteristics of included studies.

1. Summary of characteristics of included studies.

Study characteristics	Criteria	N= 27^a	%
Study design	Parallel	16	59%
Study design	Cross‐over	11	41%
Sponsorship	Pharmaceutical	19	70%
	Non‐pharmaceutical	5	19%
	Unclear	3	11%
Age inclusion criteria	Adolescents (12‐17 years)	17	63%
	Children and adolescents	6	22%
	Children (< 12 years)	4	15%
Pain scale	4‐point scale	21	78%
	5‐faces scale	5	18%
	VAS	1	4%
Preventive medication permitted?	Yes	9	33%
	No	13	48%
	Unclear	5	19%
Route of delivery	Oral	19	70%
Route of delivery	Intranasal	8	30%
Medications	Paracetamol	1	4%
	Ibuprofen	3	7%
	Triptans	24	85%
	DHE	1	4%
Triptan medications	Almotriptan	1	4%
	Eletriptan	1	4%
	Naratriptan	1	4%
	Rizatriptan	4	17%
	Sumatriptan	12	50%
	Sumatriptan + naproxen sodium	1	4%
	Zolmitriptan	4	17%

Review Manager ID	Study design	Agent	Route	Child. (< 12 yrs)	Adolesc. (12‐17 yrs)	Mean age	No	% Female
Paracetamol
Hämäläinen 1997a	Cross‐over	—	PO	Yes	Yes	10.7	80	50%
Ibuprofen
Hämäläinen 1997a	Cross‐over	—	PO	Yes	Yes	10.7	78	50%
Lewis 2002	Parallel	—	PO	Yes	No	9.0	84	ND
Evers 2006	Cross‐over	—	PO	Yes	Yes	13.9	29	56%
Triptans (< 12 years)
Ho 2012	Parallel	Rizatriptan	PO	Yes	NA	ND	200	44%
Ueberall 1999	Cross‐over	Sumatriptan	IN	Yes	No	8.2	14	50%
Hämäläinen 2002	Cross‐over	Sumatriptan	IN	Yes	No	9.7	59	54%
Triptans (12‐17 years)
Linder 2008	Parallel	Almotriptan	PO	No	Yes	14.4	714	60%
Winner 2007	Parallel	Eletriptan	PO	No	Yes	14.0	274	57%
Rothner 1997	Parallel	Naratriptan	PO	No	Yes	14.3	300	54%
Ho 2012	Parallel	Rizatriptan	PO	NA	Yes	ND	570	61%
Visser 2004a	Parallel	Rizatriptan	PO	No	Yes	14.2	476	55%
Winner 2002	Parallel	Rizatriptan	PO	No	Yes	14.0	296	54%
Ahonen 2006	Cross‐over	Rizatriptan	PO	Yes	Yes	12.0	116	54%
Callenbach 2007	Cross‐over	Sumatriptan	IN	No	Yes	13.6	46	78%
Rothner 1999b	Parallel	Sumatriptan	PO	No	Yes	13.6	92	52%
Winner 2000	Parallel	Sumatriptan	IN	No	Yes	14.1	507	52%
Hämäläinen 1997b	Cross‐over	Sumatriptan	PO	Yes	Yes	12.3	23	52%
Rothner 1999c	Parallel	Sumatriptan	PO	No	Yes	13.5	102	42%
Fujita 2014	Parallel	Sumatriptan	PO	Yes	Yes	14.1	144	58%
Winner 1997	Cross‐over	Sumatriptan	PO	No	Yes	13.9	298	58%
Winner 2006	Parallel	Sumatriptan	IN	No	Yes	14.3	731	55%
Ahonen 2004	Cross‐over	Sumatriptan	IN	Yes	Yes	12.4	94	46%
Rothner 1999a	Parallel	Sumatriptan	PO	No	Yes	14.1	273	57%
Derosier 2012	Parallel	Sumatriptan and Naproxen Sodium	PO	No	Yes	14.7	490	59%
Lewis 2007	Cross‐over	Zolmitriptan	IN	No	Yes	14.2	171	57%
Evers 2006	Cross‐over	Zolmitriptan	PO	Yes	Yes	13.9	29	56%
Rothner 2006	Parallel	Zolmitriptan	PO	No	Yes	14.2	696	59%
NCT01211145	Parallel	Zolmitriptan	IN	No	Yes	14	584	ND
Dihydroergotamine
Hämäläinen 1997c	Cross‐over	—	PO	Yes	Yes	10.3	13	38%

Ibuprofen compared with placebo in children with migraine
Patient or population: acute treatment of migraine in children Setting: ambulatory Intervention: ibuprofen Comparison: placebo
Outcomes	Anticipated absolute effects^a (95% CI)		Relative effect (95% CI)	No of participants (studies)	Quality of the evidence (GRADE)
	Response with placebo	Response with Ibuprofen
Pain freedom at 2 h	Study population		RR 1.87 (1.15 to 3.04)	125 (2 RCTs)	⨁⨁◯◯^b,c Low
	267 per 1000	499 per 1000 (307 to 811)
Adverse events	100 per 1000	0 per 1000 (− 13 to 13)	RD 0.00 (− 0.13 to 0.13)	80 (1 RCT)
GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low quality: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low quality: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect. CI: confidence interval; RR: risk ratio; RD: risk difference

Triptans compared with placebo in children with migraine
Patient or population: acute treatment of migraine in children Setting: ambulatory Intervention: triptans Comparison: placebo
Outcomes	Anticipated absolute effects^a (95% CI)		Relative effect (95% CI)	No of participants (studies)	Quality of the evidence (GRADE)	Comments
	Response with placebo	Response with triptans
Pain freedom at 2 h	Study population		RR 1.67 (1.06 to 2.62)	345 (3 RCTs)	⨁⨁⨁◯^b,c MODERATE	Includes rizatriptan oral (1 study) and sumatriptan by nasal spray (2 studies)
	276 per 1000	461 per 1000 (292 to 723)
Adverse events	176 per 1000	11 per 1000 (− 7 to 30)	RD 0.06 (− 0.04 to 0.17)	420 (3 RCTs)
GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate quality: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low quality: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low quality: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect. CI: confidence interval; RR: risk ratio; RD: risk difference.

Triptans compared with placebo in adolescents with migraine
Patient or population: acute treatment of migraine in adolescents Setting: ambulatory Intervention: Triptans Comparison: placebo
Outcomes	Anticipated absolute effects^a (95% CI)		Relative effect (95% CI)	No of participants (studies)	Quality of the evidence (GRADE)	Comments
	Response with placebo	Response with Triptans
Pain freedom at 2 h	Study population		RR 1.32 (1.19 to 1.47)	6761 (21 RCTs)	⨁⨁⨁◯^b,c MODERATE	Includes almotriptan (1 study), eletriptan (1 study), naratriptan (1 study), rizatriptan (4 studies), sumatriptan (10 studies), and zolmitriptan (4 studies)
	230 per 1000	303 per 1000 (273 to 338)
Adverse events	184 per 1000	24 per 1000 (15 to 33)	RD 0.13 (0.08 to 0.18)	7876 (21 RCTs)
GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate quality: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low quality: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low quality: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect. CI: confidence interval; RR: risk ratio; RD: risk difference.

Sumatriptan + naproxen sodium compared with placebo in adolescents with migraine
Patient or population: acute treatment of migraine in adolescents Setting: ambulatory Intervention: sumatriptan + naproxen sodium Comparison: placebo
Outcomes	Anticipated absolute effects^a (95% CI)		Relative effect (95% CI)	No of participants (studies)	Quality of the evidence (GRADE)	Comments
	Response with placebo	Response with Sumatriptan + naproxen sodium
Pain freedom at 2 h	Study population		RR 2.66 (1.57 to 4.51)	485 (1 RCT)	⨁⨁⨁◯^b,c MODERATE	Doses including sumatriptan + naproxen 10 mg + 60 mg, 30 mg + 180 mg, and 85 mg + 500 mg were all well tolerated and demonstrated similar efficacy
	99 per 1000	262 per 1000 (163 to 394)
Adverse events	83 per 1000	2 per 1000 (− 2 to 7)	RD 0.03 (− 0.02 to 0.09)	490 (1 RCT)
GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate quality: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low quality: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low quality: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect. CI: confidence interval; RR: risk ratio; RD: risk difference.

Date	Event	Description
17 October 2018	Review declared as stable	See Published notes.
1 September 2010	Feedback has been incorporated	Incorporated feedback from Editorial review and updated search.
15 May 2008	Amended	Converted to new review format.

Database	2008		2012		2013		2014		2016		Total
Database	Number retrieved	After duplicates removed	Number retrieved	After duplicates removed	Number retrieved	After duplicates removed	Number retrieved	After duplicates removed	Number retrieved	After duplicates removed	Number retrieved	After duplicates removed
MEDLINE	2844	2742	639	616	90	75	—	—	326	231	3899	3664
MEDLINE In‐Process	29	29	29	29	16	14	—	—	—	—	74	72
CCRT	153	126	153	126	10	2	—	—	—	—	316	254
CDSR DARE	664	650	664	650	324	169	—	—	—	—	1652	1469
IPA	109	27	40	10	7	4	—	—	—	—	156	41
PsycINFO	255	147	147	85	5	3	—	—	—	—	407	235
EMBASE	6357	5548	2884	2517	508	412	794	787	626	516	11,169	9780
CINAHL	712	190	263	70	31	21	—	—	—	—	1006	281
Total	11,123	9459	4819	4103	991	700	794	787	952	747	18,679	15,796

Database	Date Searched	Number Retrieved	After Duplicate Removal^a
EMBASE	3 February 2016	626	516
MEDLINE	3 February 2016	326	231
Total		952	747

Review	Number Retrieved	After Duplicate Removal	Update Search Date	Number Retrieved	After Duplicate Removal
MEDLINE	639	616	29 April 2013	90	75
MEDLINE In‐Process	29	29	29 April 2013	16	14
CCRT	153	127	29 April 2013	10	2
CDSR DARE	664	650	29 April 2013	324	169
IPA	40	10	29 April 2013	7	4
PsycINFO	147	85	29 April 2013	5	3
EMBASE	2,884	2,511	30 April 2013	508	411
CINAHL	213	70	30 April 2013	31	21
Total	4769	4098		991	699

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Pain‐free	2	125	Risk Ratio (M‐H, Random, 95% CI)	1.87 [1.15, 3.04]
1.2 Adverse events (any)	1	80	Risk Difference (M‐H, Random, 95% CI)	0.00 [‐0.13, 0.13]
1.3 Headache relief	2	125	Risk Ratio (M‐H, Random, 95% CI)	1.49 [1.11, 2.00]
1.4 Rescue medication	2	164	Risk Ratio (M‐H, Random, 95% CI)	0.19 [0.02, 1.56]
1.5 Headache recurrence	1	38	Risk Ratio (M‐H, Fixed, 95% CI)	0.25 [0.01, 5.68]

*Study characteristics*
Methods	Randomized, double‐blind, placebo‐controlled, parallel group trial of oral sumatriptan
Participants	Participants from 17 centres in Japan were 10‐17 years of age, diagnosed with migraine with or without aura per ICHD‐2 criteria for a minimum of 6 months, and 2‐8 attacks monthly lasting for > 3 h in the last 2 months prior to entry. Randomized (N = 178); withdrawn (N = 34); intention‐to‐treat and primary efficacy analysis (N = 144)
Interventions	Oral sumatriptan 25 mg (1 tablet and 1 matching placebo), sumatriptan 50 mg (2 tablets), or placebo (2 tablets) taken as soon as possible (within 30 minutes) after the development of a migraine with grade 3 or more pain
Outcomes	Headache relief (reduction of 2 grades) at 2 h Pain‐free at 2 h Presence of nausea, vomiting at 2 h Use of rescue medications from time of dosing to 4 h post‐treatment Adverse events Other reported outcomes: Headache relief, pain‐free, photophobia, phonophobia, and vomiting at 0.5, 1, and 4 hours post‐treatment
Headache severity scale	5‐grade scale
Funding source	GlaxoSmithKline
Publication	Journal and Clinical Trial Registry
Notes	—
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Investigator (or subinvestigator) completed the registration form and sent it to the randomization center by facsimile. The randomization center. . . assigned a randomization number to the patient."
Allocation concealment (selection bias)	Low risk	Quote: "For allocation of the participants, a computer‐generated list of random numbers was used."
Blinding (performance bias and detection bias) All outcomes	Low risk	Quote: "The investigator (or subinvestigator) dispensed the investigational product to the patient according to the computer‐generated randomization number."
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: used last observation carried forward (LOCF)
Selective reporting (reporting bias)	Low risk	Comment: all stated outcomes were reported

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 Pain‐free	3	345	Risk Ratio (M‐H, Random, 95% CI)	1.67 [1.06, 2.62]
2.1.1 Rizatriptan	1	200	Risk Ratio (M‐H, Random, 95% CI)	1.31 [0.89, 1.92]
2.1.2 Sumatriptan	2	145	Risk Ratio (M‐H, Random, 95% CI)	2.29 [1.00, 5.23]
2.2 Adverse events (any)	3	420	Risk Difference (M‐H, Random, 95% CI)	0.06 [‐0.04, 0.17]
2.2.1 Rizatriptan	1	275	Risk Difference (M‐H, Random, 95% CI)	0.00 [‐0.09, 0.09]
2.2.2 Sumatriptan	2	145	Risk Difference (M‐H, Random, 95% CI)	0.13 [0.01, 0.26]
2.3 Headache relief	3	345	Risk Ratio (M‐H, Random, 95% CI)	1.36 [0.88, 2.08]
2.3.1 Rizatriptan	1	200	Risk Ratio (M‐H, Random, 95% CI)	0.97 [0.75, 1.24]
2.3.2 Sumatriptan	2	145	Risk Ratio (M‐H, Random, 95% CI)	1.65 [1.21, 2.26]
2.4 Rescue medication	2	145	Risk Ratio (M‐H, Random, 95% CI)	0.31 [0.06, 1.45]
2.4.1 Sumatriptan	2	145	Risk Ratio (M‐H, Random, 95% CI)	0.31 [0.06, 1.45]
2.5 Headache recurrence	1	18	Risk Ratio (M‐H, Random, 95% CI)	Not estimable
2.5.1 Sumatriptan	1	18	Risk Ratio (M‐H, Random, 95% CI)	Not estimable
2.6 Presence of nausea	3	345	Risk Ratio (M‐H, Random, 95% CI)	0.64 [0.46, 0.90]
2.6.1 Rizatriptan	1	200	Risk Ratio (M‐H, Random, 95% CI)	0.68 [0.38, 1.22]
2.6.2 Sumatriptan	2	145	Risk Ratio (M‐H, Random, 95% CI)	0.62 [0.42, 0.94]
2.7 Presence of vomiting	3	345	Risk Ratio (M‐H, Random, 95% CI)	0.50 [0.13, 1.86]
2.7.1 Rizatriptan	1	200	Risk Ratio (M‐H, Random, 95% CI)	1.73 [0.43, 7.06]
2.7.2 Sumatriptan	2	145	Risk Ratio (M‐H, Random, 95% CI)	0.30 [0.09, 0.99]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
3.1 Pain‐free	21	6761	Risk Ratio (M‐H, Random, 95% CI)	1.32 [1.19, 1.47]
3.1.1 Almotriptan	1	714	Risk Ratio (M‐H, Random, 95% CI)	1.10 [0.88, 1.39]
3.1.2 Eletriptan	1	274	Risk Ratio (M‐H, Random, 95% CI)	1.46 [0.88, 2.43]
3.1.3 Naratriptan	1	300	Risk Ratio (M‐H, Random, 95% CI)	1.06 [0.65, 1.75]
3.1.4 Rizatriptan	4	1526	Risk Ratio (M‐H, Random, 95% CI)	1.34 [1.13, 1.60]
3.1.5 Sumatriptan	10	2415	Risk Ratio (M‐H, Random, 95% CI)	1.27 [1.10, 1.48]
3.1.6 Zolmitriptan	4	1532	Risk Ratio (M‐H, Random, 95% CI)	1.66 [1.16, 2.38]
3.2 Adverse events (any)	21	7876	Risk Difference (M‐H, Random, 95% CI)	0.13 [0.08, 0.18]
3.2.1 Almotriptan	1	720	Risk Difference (M‐H, Random, 95% CI)	0.05 [0.00, 0.09]
3.2.2 Eletriptan	1	242	Risk Difference (M‐H, Random, 95% CI)	0.14 [0.02, 0.26]
3.2.3 Naratriptan	1	300	Risk Difference (M‐H, Random, 95% CI)	0.16 [0.05, 0.27]
3.2.4 Rizatriptan	4	1706	Risk Difference (M‐H, Random, 95% CI)	0.04 [‐0.02, 0.10]
3.2.5 Sumatriptan	10	2969	Risk Difference (M‐H, Random, 95% CI)	0.18 [0.09, 0.27]
3.2.6 Zolmitriptan	4	1939	Risk Difference (M‐H, Random, 95% CI)	0.14 [0.07, 0.20]
3.3 Headache relief	20	6182	Risk Ratio (M‐H, Random, 95% CI)	1.14 [1.04, 1.24]
3.3.1 Almotriptan	1	714	Risk Ratio (M‐H, Random, 95% CI)	1.27 [1.10, 1.47]
3.3.2 Eletriptan	1	277	Risk Ratio (M‐H, Random, 95% CI)	0.96 [0.79, 1.17]
3.3.3 Naratriptan	1	300	Risk Ratio (M‐H, Random, 95% CI)	0.80 [0.65, 1.00]
3.3.4 Rizatriptan	4	1526	Risk Ratio (M‐H, Random, 95% CI)	1.24 [0.99, 1.56]
3.3.5 Sumatriptan	10	2392	Risk Ratio (M‐H, Random, 95% CI)	1.14 [1.02, 1.28]
3.3.6 Zolmitriptan	3	973	Risk Ratio (M‐H, Random, 95% CI)	1.21 [0.87, 1.69]
3.4 Rescue medication	18	5066	Risk Ratio (M‐H, Random, 95% CI)	0.79 [0.72, 0.87]
3.4.1 Almotriptan	1	714	Risk Ratio (M‐H, Random, 95% CI)	0.57 [0.28, 1.16]
3.4.2 Eletriptan	1	277	Risk Ratio (M‐H, Random, 95% CI)	0.82 [0.59, 1.12]
3.4.3 Naratriptan	1	300	Risk Ratio (M‐H, Random, 95% CI)	0.92 [0.55, 1.53]
3.4.4 Rizatriptan	3	956	Risk Ratio (M‐H, Random, 95% CI)	0.74 [0.55, 1.01]
3.4.5 Sumatriptan	10	2451	Risk Ratio (M‐H, Random, 95% CI)	0.80 [0.70, 0.92]
3.4.6 Zolmitriptan	2	368	Risk Ratio (M‐H, Random, 95% CI)	0.55 [0.20, 1.52]
3.5 Headache recurrence	15	2463	Risk Ratio (M‐H, Random, 95% CI)	0.79 [0.68, 0.93]
3.5.1 Almotriptan	1	477	Risk Ratio (M‐H, Random, 95% CI)	1.13 [0.44, 2.89]
3.5.2 Eletriptan	1	161	Risk Ratio (M‐H, Random, 95% CI)	0.81 [0.53, 1.23]
3.5.3 Naratriptan	1	201	Risk Ratio (M‐H, Random, 95% CI)	0.84 [0.42, 1.67]
3.5.4 Rizatriptan	1	177	Risk Ratio (M‐H, Random, 95% CI)	0.63 [0.30, 1.32]
3.5.5 Sumatriptan	9	1319	Risk Ratio (M‐H, Random, 95% CI)	0.78 [0.65, 0.94]
3.5.6 Zolmitriptan	2	128	Risk Ratio (M‐H, Random, 95% CI)	0.98 [0.36, 2.65]
3.6 Presence of nausea	17	4975	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.79, 1.12]
3.6.1 Almotriptan	1	356	Risk Ratio (M‐H, Random, 95% CI)	1.45 [1.04, 2.02]
3.6.2 Eletriptan	1	277	Risk Ratio (M‐H, Random, 95% CI)	0.96 [0.84, 1.09]
3.6.3 Naratriptan	1	300	Risk Ratio (M‐H, Random, 95% CI)	1.08 [0.66, 1.78]
3.6.4 Rizatriptan	2	1060	Risk Ratio (M‐H, Random, 95% CI)	0.63 [0.49, 0.80]
3.6.5 Sumatriptan	10	2279	Risk Ratio (M‐H, Random, 95% CI)	1.01 [0.78, 1.29]
3.6.6 Zolmitriptan	2	703	Risk Ratio (M‐H, Random, 95% CI)	0.39 [0.04, 4.02]
3.7 Presence of vomiting	12	4037	Risk Ratio (M‐H, Random, 95% CI)	0.73 [0.48, 1.12]
3.7.1 Almotriptan	0	0	Risk Ratio (M‐H, Random, 95% CI)	Not estimable
3.7.2 Eletriptan	0	0	Risk Ratio (M‐H, Random, 95% CI)	Not estimable
3.7.3 Naratriptan	1	300	Risk Ratio (M‐H, Random, 95% CI)	1.96 [0.24, 16.05]
3.7.4 Rizatriptan	1	769	Risk Ratio (M‐H, Random, 95% CI)	0.51 [0.22, 1.18]
3.7.5 Sumatriptan	8	2265	Risk Ratio (M‐H, Random, 95% CI)	0.68 [0.39, 1.20]
3.7.6 Zolmitriptan	2	703	Risk Ratio (M‐H, Random, 95% CI)	1.12 [0.79, 1.58]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
4.1 Pain‐free by route (oral or intranasal)	21	6764	Risk Ratio (M‐H, Random, 95% CI)	1.32 [1.19, 1.47]
4.1.1 Oral	15	4415	Risk Ratio (M‐H, Random, 95% CI)	1.22 [1.08, 1.38]
4.1.2 Intranasal	6	2349	Risk Ratio (M‐H, Random, 95% CI)	1.52 [1.32, 1.75]
4.2 Sumatriptan vs placebo by route (oral or intranasal)	10	2415	Risk Ratio (M‐H, Random, 95% CI)	1.27 [1.10, 1.48]
4.2.1 Intranasal	4	1490	Risk Ratio (M‐H, Random, 95% CI)	1.37 [1.15, 1.63]
4.2.2 Oral	6	925	Risk Ratio (M‐H, Random, 95% CI)	1.03 [0.75, 1.43]
4.3 Zolmitriptan vs placebo by route (oral or intranasal)	4	1532	Risk Ratio (M‐H, Random, 95% CI)	1.66 [1.16, 2.38]
4.3.1 Intranasal	2	859	Risk Ratio (M‐H, Random, 95% CI)	1.87 [1.46, 2.40]
4.3.2 Oral	2	673	Risk Ratio (M‐H, Random, 95% CI)	1.94 [0.42, 9.07]
4.4 Pain‐free by preventive medication	21	6764	Risk Ratio (M‐H, Random, 95% CI)	1.32 [1.19, 1.47]
4.4.1 Preventive medication not permitted	8	1658	Risk Ratio (M‐H, Random, 95% CI)	1.39 [1.14, 1.69]
4.4.2 Preventive medication permitted	8	2316	Risk Ratio (M‐H, Random, 95% CI)	1.28 [1.04, 1.56]
4.4.3 Unsure	5	2790	Risk Ratio (M‐H, Random, 95% CI)	1.33 [1.11, 1.61]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
5.1 Age group	23		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
5.1.1 Children	3	345	Risk Ratio (M‐H, Random, 95% CI)	1.67 [1.06, 2.62]
5.1.2 Mixed children and adolescents	5	606	Risk Ratio (M‐H, Random, 95% CI)	1.69 [0.96, 2.98]
5.1.3 Adolescent	16	6188	Risk Ratio (M‐H, Random, 95% CI)	1.31 [1.18, 1.45]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
6.1 Study design	21	6794	Risk Ratio (M‐H, Random, 95% CI)	1.33 [1.19, 1.49]
6.1.1 Cross‐over	7	1127	Risk Ratio (M‐H, Random, 95% CI)	1.81 [1.44, 2.26]
6.1.2 Parallel	14	5667	Risk Ratio (M‐H, Random, 95% CI)	1.25 [1.12, 1.39]
6.2 Allocation concealment	21		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
6.2.1 Low	8	2365	Risk Ratio (M‐H, Random, 95% CI)	1.50 [1.19, 1.89]
6.2.2 Unclear	13	4429	Risk Ratio (M‐H, Random, 95% CI)	1.25 [1.12, 1.40]
6.3 Source of funding	21		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
6.3.1 Pharmaceutical	17	6332	Risk Ratio (M‐H, Random, 95% CI)	1.29 [1.16, 1.43]
6.3.2 Non‐pharmaceutical	2	104	Risk Ratio (M‐H, Random, 95% CI)	4.22 [1.50, 11.84]
6.3.3 Unclear	2	358	Risk Ratio (M‐H, Random, 95% CI)	1.76 [1.22, 2.54]
6.4 Reported in a journal	21		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
6.4.1 Journal report	15	5175	Risk Ratio (M‐H, Random, 95% CI)	1.34 [1.18, 1.52]
6.4.2 Registry or abstract only	6	1619	Risk Ratio (M‐H, Random, 95% CI)	1.26 [0.94, 1.71]
6.5 Sample size	21	6794	Risk Ratio (M‐H, Random, 95% CI)	1.33 [1.19, 1.49]
6.5.1 Sample size ≤ 50	2	104	Risk Ratio (M‐H, Random, 95% CI)	4.22 [1.50, 11.84]
6.5.2 Sample size > 50	19	6690	Risk Ratio (M‐H, Random, 95% CI)	1.31 [1.18, 1.46]

*Study characteristics*
Methods	Randomized, placebo‐controlled, double‐blind, 3‐way cross‐over trial of oral rizatriptan
Participants	Children or adolescents between 6 and 17 years of age, body weight ≥ 20 kg, headache meeting the IHS 1988 criteria for migraine with or without aura from the 2 pediatric hospitals in Finland. Participants were expected to have at least 2 migraine attacks per month lasting 4 h or more and previous unsatisfactory with paracetamol or NSAIDs. None of the children were receiving preventive therapy. Randomized (N = 147); medication not used (N = 31); 1 medication used (N = 10); 2 treatments used (N = 10); intention‐to‐treat analysis (N = 116); primary efficacy analysis (N = 96)
Interventions	Rizatriptan 5 mg (weight 20 to 39 kg) or rizatriptan 10 mg (weight ≥ 40 kg) and placebo. Each participant treated 3 migraine attacks (2 with rizatriptan and 1 with placebo) at the onset of the attack if headache severity was ≥ 3 on the 5‐point scale. Rescue medications were allowed at any time, but encouraged to be taken only after 2 h.
Outcomes	Headache relief at 2 h (defined as severe or moderate (a grade of ≥ 3) to at least 2 grades lower or fell asleep during these 2 h and was pain‐free on awakening) Pain‐free at 2h Adverse events Use of rescue medication Other reported outcomes: Headache relief and pain‐free at 1, 3, and 4 h after treatment Participant preference
Headache severity scale	5‐faces pain scale (5 severe, 4 to 3 moderate, 2 mild, 1 no pain)
Funding source	Not specified
Publication	Journal
Notes	All children who had used at least 1 treatment were included in the intention‐to‐treat analysis
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "tossing a coin method"
Allocation concealment (selection bias)	Low risk	Quote: "Randomization was done in the hospital pharmacy"; "randomization code was stored by one of the authors. . . was not broken until the database of treatment efficacy was created and locked"
Blinding (performance bias and detection bias) All outcomes	Low risk	Quote: "drugs packed in capsules of identical appearance"
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: missing outcome data balanced across intervention groups
Selective reporting (reporting bias)	Low risk	Comment: all expected outcomes reported

*Study characteristics*
Methods	Outpatient, double‐blind, randomized, placebo‐controlled, parallel group trial with an enrichment design of oral sumatriptan + naproxen sodium
Participants	Eligible participants were 12 to 17 years old at screening and had > 6 months history of 2 to 8 migraine attacks per month (with or without aura: ICHD‐2), typically lasting > 3 h and associated with moderate to severe headache pain. Triptan‐naïve subjects were eligible. Run‐in phase (N = 976); Randomized (N = 589); Medication not used (N = 57); Withdrawn (N = 42); intention‐to‐treat and primary efficacy analysis (N = 490)
Interventions	Subjects treating 1 moderate to severe migraine with single‐blind placebo during the run‐in phase and reporting pain 2 h post dose (placebo non responders) were randomly assigned into the double‐blind phase. In the double‐blind phase, subjects treated 1 moderate to severe migraine with either matching placebo or sumatriptan + naproxen sodium 10 mg + 60 mg, 30 mg + 180 mg, or 85 mg + 500 mg.
Outcomes	Pain‐free at 2 h post‐treatment in the double‐blind phase (absence of headache pain post‐treatment from moderate or severe at baseline, without previous use of rescue medication) Nausea free at 2 h Use of rescue medication within 2‐24 h Other reported outcomes: Sustained freedom from pain, photophobia, phonophobia, and nausea from 2‐24 h post‐treatment
Headache severity scale	4‐level pain scale (none, mild, moderate, severe)
Funding source	GlaxoSmithKline
Publication	Journal and Clinical Trial Registry
Notes	Single‐blind run‐in phase (enrichment design) assessment was at 2 h
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "Upon determination of subject eligibility and completion of the randomizations visit, site staff telephoned an interactive voice response system and dispensed randomly assigned, age‐group stratified treatment."
Allocation concealment (selection bias)	Low risk	Comment: used interactive voice response system for randomization
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Parent/guardian and subject were informed that they would not know which study drug was provided for the first or second migraine treated, and that the investigator would not know which study drug was provided for the second migraine treated. To maintain blinding, sites received education on describing the single‐blind phase.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: withdrawals and reasons for withdrawal (outlined in Figure 1 of Derosier 2012) were balanced between groups
Selective reporting (reporting bias)	Low risk	Comment: all expected outcomes were reported

*Study characteristics*
Methods	Double‐blind, placebo‐controlled, cross‐over study to investigate the efficacy of oral zolmitriptan in the treatment of migraine attacks in children and adolescents
Participants	Children and adolescents aged 6‐18 years from an headache outpatient clinic (not reported separately) Migraine with and without aura according to the criteria of the ICHD‐2 No neurologic, psychiatric, and vascular disorder Randomized (N = 32); withdrawn (N = 3); intention‐to‐treat and primary efficacy analysis (N = 29)
Interventions	Ibuprofen 200 mg PO (children under 12) or 400 mg PO (adolescents) Zolmitriptan 2.5 mg PO
Outcomes	Pain relief (defined as no or mild headache after moderate or severe headache) after 2 h Pain free after 2 h Headache recurrence and use of rescue medication within 24 h Nausea and vomiting after 2 h All adverse events classified (probably/possibly drug related or not drug related) Other reported outcomes: Pain‐free and headache relief after 0.5, 1, 4, and 24 h Headache recurrence, sustained pain‐free response, frequency of accompanying symptoms (nausea, vomiting, photophobia, phonophobia) after 0.5, 1, 3, and 24 h
Headache severity scale	4‐point scale (none, mild, moderate, severe)
Funding source	Not clear
Publication	Journal
Notes	—
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "The order of the study drugs was randomized for every patient."
Allocation concealment (selection bias)	Low risk	Comment: cross‐over study where each participant received the study drugs in random order
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Comment: blinding was not reported
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: 3 of 32 participants dropped out (withdrawal of consent N = 2) lost to follow‐up N = 1)
Selective reporting (reporting bias)	Low risk	Comment: aAll primary and secondary outcomes were reported

*Study characteristics*
Methods	Multicenter, randomized, double‐blind, placebo‐controlled, 2‐way, 2‐attack, cross‐over study of zolmitriptan nasal spray with a single‐blind 'placebo challenge' or 'enrichment' phase
Participants	Adolescents of age 12‐17 years with a diagnosis of migraine with or without aura per the IHS 1988 criteria or revised IHS‐1988 criteria (Winner 1995) with a frequency of 2 or more migraine attacks per month during the school year and < 14 days per month without migraine for the 3 months before screening. The usual duration of untreated migraine was required to be > 2 h. Participants were permitted to use preventive medication that had been stable for 2 months before randomization. Randomized (N = 248); withdrawn (N = 34); placebo responder to both attacks (N = 12); placebo responder to 1 attack (N = 12); missing efficiency data (N = 19); intention‐to‐treat analysis (N = 171)
Interventions	Each participant treated 1 migraine attack with zolmitriptan 5 mg nasal spray and another with matching placebo within a 12‐week period. Each attack was treated initially with placebo normal saline within 30 min after the headache reached moderate or severe intensity. If migraine intensity remained moderate or severe, then participants were randomly assigned to use zolmitriptan or matching placebo (1:1). A second dose of randomized treatment or approved escape medications were permitted 2 h after the first dose if moderate or severe pain persisted.
Outcomes	Headache relief (decrease from moderate or severe to mild or no headache) at 2 h (1 h was used as the primary outcome in the study) Pain‐free at 2 h Use of rescue medication Presence of nausea Use of rescue medications within 2 h Adverse events Other reported outcomes: Presence of photophobia and phonophobia Other time points including 15, 30, 45, 60, and 90 min
Headache severity scale	4‐point scale (none, mild, moderate, severe)
Funding source	AstraZeneca
Publication	Journal and clinical trial registry
Notes	—
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "Patients were randomly assigned strictly sequentially"
Allocation concealment (selection bias)	Low risk	Quote: "double‐blind randomization schedule (prepared by the study sponsor)"
Blinding (performance bias and detection bias) All outcomes	Low risk	Quote: "matching placebo" Comment: unique study design with placebo challenge where all subjects initially received placebo in a single‐blind (participant) fashion. Only those who did not respond were randomly assigned to active drug or placebo.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: missing outcome data distributed evenly across intervention groups
Selective reporting (reporting bias)	Low risk	Comment: all expected outcomes reported

*Study characteristics*
Methods	Randomized, double‐blind, parallel‐group, placebo‐controlled trial of oral eletriptan
Participants	Participants were 12‐17 years, met ICHD‐2 criteria for migraine with or without aura, and suffered at least 1 migraine attack every 6 weeks. Mean migraine duration was required to be a minimum of 4 h. Randomized (N = 348); did not receive study medication (N = 74); intention‐to‐treat and primary efficacy analysis (N = 274)
Interventions	Eletriptan 40 mg PO, placebo taken within 4 h of headache onset
Outcomes	Headache relief at 2 h (reduction from moderate or severe to mild or no pain) Pain‐free at 2 h Presense of nausea Use of rescue medications (within 24 h) Headache recurrence (within 2 to 24 h) Adverse events Other reported outcomes: Headache relief and pain‐free at 1 h Presence of photophobia or phonophobia Change in functional impairment Migraine‐free (no headache and no associated symptoms at 2 h Acceptability of medication
Headache severity scale	4‐level (none, mild, moderate, severe)
Funding source	Pfizer
Publication	Journal
Notes	—
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: no information provided
Allocation concealment (selection bias)	Unclear risk	Comment: no information provided
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Comment: described as "placebo‐controlled", but no other description
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: "Three hundred and eighty‐four were screened, of whom 348 were randomized to study drug . . ."; "Seventy‐four were randomized but did not take the study drug: (1) 35 did not treat a migraine attack during the 12‐week time window. . ." Comment: withdrawals balanced across intervention groups
Selective reporting (reporting bias)	Low risk	Comment: all expected outcomes reported; originally published as an abstract in 2000 (Pitman 2000) followed by this full report.

PERMALINK

Drugs for the acute treatment of migraine in children and adolescents

Lawrence Richer

Lori Billinghurst

Meghan A Linsdell

Kelly Russell

Ben Vandermeer

Ellen T Crumley

Tamara Durec

Terry P Klassen

Lisa Hartling

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Background

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Primary outcomes

Secondary outcomes

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Assessment of quality of evidence in included studies

'Summary of findings' table

Measures of treatment effect

Unit of analysis issues

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

Results

Description of studies

Results of the search

1.

Included studies

1. Summary of characteristics of included studies.

2. Summary table of included studies.

Excluded studies

Awaiting classification

Risk of bias in included studies

2.

3.

Allocation

Blinding

Incomplete outcome data

Selective reporting

Other potential sources of bias

4.

Effects of interventions

Summary of findings 1. Should ibuprofen be used to treat children with migraine?

Summary of findings 2. Should triptans be used to treat children with migraine?

Summary of findings 3. Should triptans be used to treat adolescents with migraine?

Summary of findings 4. Should sumatriptan plus naproxen sodium be used to treat adolescents with migraine?

Paracetamol versus placebo in children

Ibuprofen versus placebo in children

5.

1.1. Analysis.

1.3. Analysis.

1.4. Analysis.

1.5. Analysis.

1.2. Analysis.

Ibuprofen versus placebo in adolescents

Study	Reason for exclusion
Brousseau 2004	The Emergency Department setting and parenteral interventions studied (intravenous prochlorperazine versus ketorolac) were significantly different from included clinical trials of interventions in the outpatient setting. As there were few other clinical trials in the Emergency Department setting, we made a post hoc decision to exclude this study to simplify the review conclusions.
Cady 2011	Non‐drug clinical trial and participants were not exclusively pediatric
Gertsch 2011	Open‐label, uncontrolled study
NCT00355394	The Emergency Department setting and parenteral intervention studied (intravenous metoclopramide) was significantly different from included clinical trials of interventions in the outpatient setting. As there were few other clinical trials in the Emergency Department setting, we made a post hoc decision to exclude this study to simplify the review conclusions.
Soriani 2001	A non‐placebo‐controlled randomized study comparing paracetamol and nimesulide. Each of 60 participants in the study treated 10 attacks, and the primary outcome of headache relief was reported as a percentage of attacks. No individual participant data was reported so was not included in the meta‐analysis.
SUM40090	Open‐label, uncontrolled study
Trautmann 2010	Non‐drug clinical trial
Winner 2011	Study of rapid disintegrating formulation of sumatriptan was not a randomized controlled trial